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WO1993008818A1 - Compositions et procedes permettant d'eviter la formation d'adherences - Google Patents

Compositions et procedes permettant d'eviter la formation d'adherences Download PDF

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Publication number
WO1993008818A1
WO1993008818A1 PCT/US1992/009494 US9209494W WO9308818A1 WO 1993008818 A1 WO1993008818 A1 WO 1993008818A1 US 9209494 W US9209494 W US 9209494W WO 9308818 A1 WO9308818 A1 WO 9308818A1
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WIPO (PCT)
Prior art keywords
gly
ser
asp
arg
pro
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PCT/US1992/009494
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English (en)
Inventor
Gere Stodder Dizerega
Kathleen Elizabeth Rodgers
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The University Of Southern California
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University Of Southern California filed Critical The University Of Southern California
Priority to DE69229004T priority Critical patent/DE69229004D1/de
Priority to EP92924282A priority patent/EP0667783B1/fr
Publication of WO1993008818A1 publication Critical patent/WO1993008818A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof

Definitions

  • the present invention relates to the medical arts.
  • the present invention is directed to compositions and methods for use in preventing the formation of postoperative adhesions.
  • Adhesion formation in particular following peritoneal surgery, is a major source of postoperative morbidity and mortality. Appendectomy and gynecologic surgery are the most frequent surgical procedures implicated in clinically significant adhesion formation. The most serious complication of intraperitoneal adhesions is intestinal obstruction; in addition, adhesions are associated with 0 chronic or recurrent pelvic pain and infertility in females.
  • the pathogenesis of adhesion formation is complex and not entirely understood.
  • the first step is believed to involve excess fibrin deposition to form a scaffold.
  • Various approaches for the prevention of adhesion formation have been actively explored. In general, the treatments fall into three categories: prevention of fibrin deposition in the peritoneal exudate; reduction of local tissue inflammation; and removal of fibrin deposits.
  • SUBSTITUTE SHEET Barrier agents which have been employed include both mechanical barriers and viscous solutions. Mixed results have been obtained using a barrier comprising a thin sheet of expanded polytetrafhioro-ethylene; in any event, such a membrane is less than ideal, as it must be sutured into place and is nonabsorbable. While an absorbable barrier (for example, a barrier made of oxidized regenerated cellulose) would be preferable, not all studies have demonstrated the efficacy of such barriers in preventing adhesions. Liquid barriers have also been considered for use in preventing adhesions; for example, chondroitin sulfate and carboxymethyl cellulose have both shown some promise in animal models.
  • Anti-inflammatory drugs have been evaluated for their effects on postoperative adhesion formation, as they may limit the release of fibrinous exudate in response to inflammation at the surgical site.
  • Two general classes of these drugs were tested: corticosteroids and nonsteroidal anti-inflammatory drugs.
  • corticosteroids The results of corticosteroid use in animal studies have generally not been encouraging, and clinical use of corticosteroids is limited by their other pharmacologic properties. While experimental evaluations of nonsteroidal anti- inflammatory drugs in postoperative adhesion formation show promise, clinical evaluations of these drugs for adhesion prevention is needed.
  • proteolytic enzymes e.g., pepsin, trypsin and papain
  • these enzymes are rapidly neutralized by peritoneal exudates rendering them virtually useless for adhesion prophylaxis.
  • fibrinolytics for example, fibrinolysin, streptokinase and urokinase
  • a potential complication to the clinical use of these enzymes in postoperative therapy is excessive bleeding resulting from their administration.
  • compositions for the minimization or prevention of adhesion formation comprising at least one peptide containing the amino acid sequence Arg-Gly-Asp in a drug delivery system which maintains an effective concentration of the peptide at a site of potential adhesion formation.
  • the peptide containing the requisite amino acid sequence is further characterized in that it inhibits platelet aggregation and does not induce inflammation or trauma at the site of administration.
  • adhesion formation is minimized or prevented by administration of at least one peptide containing the amino acid sequence Arg-Gly-Asp at a site of potential adhesion formation for a period of time sufficient to permit substantial tissue repair (e.g., re-epithelialization or mesothelial repair) at the site.
  • tissue repair e.g., re-epithelialization or mesothelial repair
  • inventive composition and method are useful in minimizing or preventing adhesion formation, the most common cause of which is prior surgery.
  • the inventive composition and method have been shown to be particularly effective in preventing adhesion formation in the peritoneum following surgery.
  • the present invention finds utility in other contexts, e.g., for cardiovascular, orthopedic, thoracic, ophthalmic, CNS and other uses, where
  • the present invention contemplates the use of at least one non-naturally- occurring peptide containing the amino acid sequence Arg-Gly-Asp (hereinafter referred to using the conventional single-letter amino acid symbols RGD).
  • the tripeptide RGD per se is contemplated for use in accordance with the present invention, as are longer peptides containing the RGD sequence, at or near either end or internally.
  • any peptide containing the intact sequence RGD and meeting the other characteristics discussed hereinafter would be suitable for use in accordance with the present invention.
  • a particularly suitable class of peptides for use in accordance with the present invention comprises heretofore identified peptides corresponding to sequences of known, naturally-occurring proteins.
  • the RGD sequence has been characterized as a site that promotes cellular attachment (cell recognition site) in fibronectin and other extracellular matrix and platelet adhesion proteins [see, e.g.. Ruoslahti, E., "Fibronectin and Its Receptors.” Ann. Rev. Biochem. 57:375 (1988)].
  • a class of glycoproteins has been identified as comprising the receptors in the cell recognition system for cell-extracellular matrix interaction. These proteins (collectively referred to as integrins) are characterized by the involvement of the
  • hybrid proteins with suitable properties combining the RGD-containing peptide with another protein may be employed in accordance with the present invention; such hybrid proteins may be suitably prepared using, e.g., recombinant DNA techniques well known to those of skill in the art.
  • sequences comprising only the typical L-form of the amino acids use may be made of sequences comprising one or more R-amino acids, homologs and/or other modified forms of amino acids.
  • the compounds for use in accordance with the present invention comprise only sequences of amino acids in a form corresponding to fragments of naturally- occurring proteins.
  • modifications and substitutions in peptide structure currently known to those skilled in the art or which may hereinafter be developed are contemplated as within the scope of the present invention.
  • peptides useful in accordance with the present invention are available commercially from Telios Pharmaceuticals, Inc., San Diego, California and Sigma Chemical Co., Saint Louis, Missouri.
  • Exemplary peptides include the following (unless otherwise indicated, the L-form of the amino acid is contemplated): Arg-Gly-Asp, Gly-Arg-Gly-Asp-Ser-Pro, Gly-Arg-Gly-Asp-Thr-Pro, Gly-Arg-Gly-Asp-D-Ser-Pro, Gly-Arg-Gly-Asp-Asn-Pro, n-methyl-Gly-Arg-Gly-Asp- Ser-Pro, Arg-Gly-Asp-Ser, Gly-Arg-Gly-Asp-Ser, Glv-Pen-Glv-Arg-Glv-Asp-Ser- Pro-Cys-Ala (cyclical) [Pierschbacher, M.D.
  • the class of RGD-containing peptides from which the peptides suitable for use in accordance with the present invention may be selected comprises non-naturally occurring peptides including the amino acid sequence
  • peptides from which those suitable for use in accordance with the present invention may be selected include, but are not limited to, the peptides of U.S. Patent 4,792,525 including the amino acid sequence Arg-Gly-Asp-R, wherein R is Ser, Cys or Thr.
  • Peptides suitable for use in accordance with the present invention are characterized by utility in inhibiting platelet aggregation. This utility may be evaluated using a number of different procedures which are known to those working in the field. One procedure whereby platelet aggregation is measured uses washed platelets isolated from fresh human blood drawn into acid-citrate- dextrose by differential centrifugation and gel filtration.
  • the platelets are resuspended into modified Tyrode's buffer containing 2% bovine serum albumin, pH 7.2. Aggregation can be measured using an aggregometer at 37° C at a stirring rate of 1000 rpm.
  • the reaction mixture consists of 400 ⁇ l buffer, 10 ⁇ l buffer of synthetic peptide, 10 ⁇ CaCl 2 (1 mM final concentration), and one or more activators of platelet aggregation, such as, fibrinogen, ADP, epinephrine or collagen.
  • a peptide suitable for use in accordance with the present invention is that it not induce chronic inflammation or trauma at the site of administration. In view of the apparent importance of inflammation in the process of adhesion formation, it is important that peptides be screened for their inflammatory propensities. For purposes of the present invention, chronic
  • SUBSTITUTE SHEET inflammation around the site of tissue repair is determined as evidenced by granuloma formation consisting of fused mononuclear phagocytes or multinucleate giant cells.
  • any RGD-containing peptide which inhibits platelet aggregation but does not induce chronic inflammation at the site of administration would be useful in reduction or prevention of adhesion formation.
  • RGD-containing peptides may inhibit adhesion formation through a variety of mechanisms. Based upon research to date, adhesion formation is believed to require the deposition of fibrin. Excess fibrin, if deposited and not removed, provides a scaffold for attachment and organization of incoming cells.
  • RGD-containing peptides may interfere with several aspects of adhesion formation.
  • Glanzmann's thrombasthenia in which platelet cohesion is defective have increased bleeding time and mucocutaneous bleeding, even though platelet count is normal. It is believed that this is due either to deficient GP Ilb-IIIa (the protein on the surface of platelets that binds fibrinogen, collagen, von Wildebrand factor, etc. and mediates platelet aggregation), or to expression of a non-functional form of this protein. Interestingly, these patients also have impaired clot retraction. This indicates that clotting can occur without platelet aggregation. Therefore, the utility of RGD-containing peptides in preventing adhesion formation can not be explained solely on the basis of their utility in inhibiting platelet aggregation. An additional activity of the RGD-containing peptides which may be
  • At least one RGD- containing peptide is maintained in an effective concentration at the site of potential adhesion formation for a period of time sufficient to permit substantial
  • SUBSTITUTE SHEET re-epithelialization While the term of administration may vary depending upon a number of factors which would be readily appreciated by those skilled in the art, in general a period of about four to about ten days, preferably about five to about seven days, would be adequate to prevent or substantially minimize adhesion formation.
  • the concentration of RGD-containing peptide may be varied over a fairly broad range.
  • concentrations of RGD-containing peptides which can be administered would be limited by efficacy at the lower end and the complication of increased bleeding at the upper end.
  • RGDV was given at a rate of 0.35, 0.68 or 1.31 ⁇ mol/min to achieve local plasma concentrations of 25, 50 and 100 ⁇ M, respectively [Cadroy, Y. et al., "RGDV Peptide Selectively Inhibits Platelet- dependent Thrombus Formation in Vivo," J.Clin. Invest.
  • SUBSTITUTE SHEET correspond to a concentration in the range of about 2.5 ⁇ g to about 4.8 ⁇ g/ml, an would deliver sufficient medicament to 100 kg of body weight.
  • the RGD-containing peptide may be administered directly in a suitable vehicle, for example phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • a macrophage may phagocytose or otherwise cause the medicament to enter into or attach to the surface of the macrophage MAC-1 integrin [Wright, S.D. et al., "C3bi receptor (complement type 3) recognizes a region of complement protein C3 containing the sequence Arg-Gly-Asp.” Proc. Nat'I Acad. Sci. 84:1965-1968 (1987); Krissansen, G.W.
  • the intraperitoneal macrophage- may discharge, release or otherwise cause the medicament to disperse at a later time. In this way, the medicament would be available to cause a therapeutic effect throughout the therapeutic interval.
  • Another process by which the medicament administered in a suitable solution such as PBS would cause the therapeutic effect is by activating, altering or otherwise causing the macrophage itself to achieve the therapeutic effect.
  • At least one RGD-containing peptide is administered in a drug-delivery system which enables the maintenance of requisite concentrations of the peptide for a period of time sufficient for re-epithelialization in a single dose delivery (for example, prior to suturing after surgery). While any suitable alternative would of course be contemplated as within the scope of the present invention, a number of drug- delivery systems would be particularly appropriate for administration of the RGD- containing peptide so as to maintain effective levels thereof over the requisite time period.
  • One suitable formulation to achieve the desired near zero-order release of the peptides comprises injectable microcapsules or microspheres prepared from a biodegradable polymer, such as poly(dl-lactide), poly(dl-lactide-co-glycolide),
  • SUBSTITUTE SHEET polycaprolactone polyglycolide, polylactic acid-co-glycolide, poly(hydroxybutyric acid), a polyortho-ester or a polyacetal.
  • injectable systems comprising microcapsules or microspheres of a diameter on the order of about 50 to about 500 ⁇ m offer advantages over other delivery systems. For example, they generally use less active agent and may be administered by paramedical personnel.
  • Microcapsules are systems comprising a polymeric wall that encloses a liquid or solid core.
  • the capsule wall usually does not react with the core material; however, it is designed to provide sufficient strength to enable normal handling without rupture while being sufficiently thin to allow a high core to wall volume ratio.
  • the capsule contents remain within the wall until released by diffusion or other means that dissolve, melt, break, rupture or remove the capsule material.
  • the capsule wall can be made to degrade and decompose in suitable environments while diffusing the core material through the capsule wall to allow for its slow, prolonged delivery.
  • the mechanism of release in biodegradable microcapsules is a combination of drug diffusion and polymer biodegradation. Therefore, the rate and duration of release are determined by microcapsule size, drug content and quality, and polymer parameters such as crystallinity, molecular weight and composition. In particular, adjustment in the amount of drug released is generally achieved by modification of capsule wall thickness, capsule diameter, or both.
  • Detailed information concerning the design, preparation and use of microspheres and microcapsules is provided by, e.g., Lewis, D.H., "Controlled Release of Bioactive Agents from Lactide/Glycolide Polymers," in Jason & Langer (eds.), Biodegradable polymers as drug delivery systems, pp. 1-41 (1990), the entire disclosure of which is hereby incorporated by reference.
  • a further approach for the single-dose delivery of RGD-containing peptides in accordance with the present invention involves the use of liposomes.
  • the encapsulation of an active agent in multilaminar vesicles (or liposomes) is a well known techmque to assist in target drug delivery and prolong drug residence.
  • a liposome-forming powdered lipid mixture is added to the desired quantity of active agent in aqueous solution (e.g., phosphate-buffered saline) to form a suspension. After a suitable hydration period, the hydrated suspension is then autoclaved to provide the liposome-active agent preparations.
  • aqueous solution e.g., phosphate-buffered saline
  • a lipid mixture suitable for formation of liposomes may be prepared from L- alpha-distearoyl phosphatidylcholine and cholesterol dissolved in chloroform, to which alpha-toco ' pherol is added; other compositions and methods for formation of liposomes would, however, also be useful for this purpose.
  • the intraperitoneal administration of liposomes containing ibuprofen or tolmetin is described in Rodgers, K. et al., "Inhibition of Postsurgical Adhesions by Liposomes Containing Nonsteroidal Antiinflammatory Drugs," Int. J. Fertil. 35:40 (1990), the entire disclosure of which is hereby incorporated by reference.
  • SUBSTITUTE SHEET peptide involves the use of so-called viscous instillates.
  • high- molecular-weight carriers are used in admixture with the active agents, giving rise to an extended structure which produces a solution with high viscosity.
  • Suitable high-molecular-weight carriers include dextran, carboxymethylcellulose and hyaluronic acid. While some studies have suggested that the use of viscous barrier solutions per se may have an advantageous effect in reducing the incidence of adhesion formation, it is believed that any such effect is of limited scope when compared to the combination of RGD-containing peptide and carrier.
  • the intraperitoneal administration of a viscous instillate comprising tolmetin is described in Abe, H. et al., "The Effect of Intraperitoneal Administration of
  • RGD-containing peptide could be directly attached to a chemical moiety which forms a viscous instillate (e.g., chondroitin sulfate), rather than simply admixed therewith [Sipes, N.J. et al, "RGD supported corneal wound healing,” Journal of Cellular Biochemistry Suppl. !5F:184 (1991)].
  • chondroitin sulfate a chemical moiety which forms a viscous instillate
  • At least one RGD-containing peptide is administered in combination with an absorbable mechanical barrier which alone reduces adhesion formation.
  • an RGD-containing peptide may be covalently or non-covalently (e.g., ionically) bound to such a barrier, or it may simply be dispersed therein.
  • a particularly suitable mechanical barrier for use in this particular embodiment of the invention comprises oxidized regenerated cellulose; one such absorbable barrier is available under the designation INTERCEED(TC7) from Johnson and Johnson Medical, Inc., New
  • the scoring range was from 0-4 + with 4 + indicating extensive adhesions; 0 indicating no adhesions. The lower the adhesion score, the less the extent of adhesion formation following surgery.
  • the ratings system used in the double uterine horn model was determined as follows:

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Abstract

Permettant d'éviter la formation d'adhérences, des compositions et procédés font appel à des doses efficaces d'un ou plusieurs peptides contenant des séquences RGD et prévenant les adhérences. On doit administrer ces compositions suffisamment longtemps pour permettre la réparation des tissus. Le peptide contenant des séquences RGD a aussi pour caractéristiques d'inhiber l'aggrégation des plaquettes et de ne pas induire d'inflammation ou de traumatisme sur le site d'administration. Pour cette dernière, on utilisera de préférence un vecteur (par exemple des microcapsules, des microsphères, des liposomes, des produits d'instillation visqueux et des barrières mécaniques absorbables), ce qui permettra de maintenir à un niveau efficace les concentrations locales dudit peptide.
PCT/US1992/009494 1991-11-07 1992-11-06 Compositions et procedes permettant d'eviter la formation d'adherences WO1993008818A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE69229004T DE69229004D1 (de) 1991-11-07 1992-11-06 Zusammensetzungen und verfahren zur verhinderung der adhäsionbildung
EP92924282A EP0667783B1 (fr) 1991-11-07 1992-11-06 Compositions et procedes permettant d'eviter la formation d'adherences

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US78923191A 1991-11-07 1991-11-07
US07/789,231 1991-11-07

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US (1) US5629294A (fr)
EP (1) EP0667783B1 (fr)
AT (1) ATE179074T1 (fr)
AU (1) AU3064892A (fr)
DE (1) DE69229004D1 (fr)
TW (1) TW269634B (fr)
WO (1) WO1993008818A1 (fr)
ZA (1) ZA928607B (fr)

Cited By (7)

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Publication number Priority date Publication date Assignee Title
WO1997006815A3 (fr) * 1995-08-15 1997-03-20 Fresenius Ag Solution rinçante aqueuse pour operations endoscopiques
EP0793965A3 (fr) * 1996-02-29 1999-02-24 Tano, Yasuo Composition prophylactique/thérapeutique pour cataracte secondaire
EP0913149A1 (fr) * 1997-10-27 1999-05-06 SSP Co., Ltd. Composition pharmaceutique à taux controlé de libération des drogues
EP1862476A3 (fr) * 2003-03-28 2008-02-13 Fuji Film Manufacturing Europe B.V. Protéines gélatineuses enrichies RGD déstinées à la prévention d'adhésion cellulaire
WO2009039989A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation du peptide gly-arg-gly-asp-asn-pro en tant qu'agent thérapeutique
WO2009039960A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation du peptide his-ser-leu-gly-lys-trp-leu-gly-his-pro-asp-lys-phe seul ou combiné au peptide gly-ard-gly-asp-asn-pro-oh en tant qu'agent thérapeutique
WO2010008792A1 (fr) * 2008-06-24 2010-01-21 Yale University Nanoparticules servant de plaquettes synthétiques et véhicules d'administration d'agent thérapeutique

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US5981719A (en) 1993-03-09 1999-11-09 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
US6090925A (en) 1993-03-09 2000-07-18 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
JP2003513682A (ja) * 1998-07-24 2003-04-15 ファーマカル、バイオテクノロジーズ、インコーポレーテッド 骨組織復元システムおよび方法
US6730775B1 (en) 1999-03-23 2004-05-04 University Of Southern California Methods for limiting scar and adhesion formation
US6312725B1 (en) 1999-04-16 2001-11-06 Cohesion Technologies, Inc. Rapid gelling biocompatible polymer composition
JP2003500171A (ja) * 1999-06-01 2003-01-07 ブリストル−マイヤーズ スクイブ カンパニー より炎症性応答の少ないフィブリンシーラントおよびこれを用いる方法
EP1257566A4 (fr) * 2000-02-11 2005-06-15 Univ Duke Procede de traitement de pathologies de l'oeil
US8415364B2 (en) * 2003-11-26 2013-04-09 Duke University Method of preventing or treating glaucoma
WO2006083260A2 (fr) 2004-04-28 2006-08-10 Angiotech Biomaterials Corporation Compositions et systemes pour la formation de biomateriaux reticules et procedes associes de preparation et d'utilisation
US9101581B2 (en) 2008-10-27 2015-08-11 Eyegene Inc. Method for treating vascular-related disease
CN101379082A (zh) 2006-01-19 2009-03-04 爱吉恩公司 治疗血管相关疾病的包含肽的药物组合物
JP2009523787A (ja) * 2006-01-19 2009-06-25 アイジーン インコーポレイテッド ペプチドを有効成分とする血管関連疾患の治療剤組成物
WO2009033736A2 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Utilisation d'un peptide comme agent thérapeutique
ES2371521T3 (es) * 2007-09-11 2012-01-04 Mondobiotech Laboratories Ag Uso del péptido phpfhlfvy (inhibidor de renina) como agente terapéutico.
US9555071B2 (en) * 2012-06-13 2017-01-31 Thien Nguyen Methods and compositions for the treatment of axonal and neuronal degeneration

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997006815A3 (fr) * 1995-08-15 1997-03-20 Fresenius Ag Solution rinçante aqueuse pour operations endoscopiques
EP0793965A3 (fr) * 1996-02-29 1999-02-24 Tano, Yasuo Composition prophylactique/thérapeutique pour cataracte secondaire
EP0913149A1 (fr) * 1997-10-27 1999-05-06 SSP Co., Ltd. Composition pharmaceutique à taux controlé de libération des drogues
US6375988B1 (en) 1997-10-27 2002-04-23 Ssp Co., Ltd. Drug composition with controlled drug release rate
EP1862476A3 (fr) * 2003-03-28 2008-02-13 Fuji Film Manufacturing Europe B.V. Protéines gélatineuses enrichies RGD déstinées à la prévention d'adhésion cellulaire
WO2009039989A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation du peptide gly-arg-gly-asp-asn-pro en tant qu'agent thérapeutique
WO2009039960A1 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation du peptide his-ser-leu-gly-lys-trp-leu-gly-his-pro-asp-lys-phe seul ou combiné au peptide gly-ard-gly-asp-asn-pro-oh en tant qu'agent thérapeutique
WO2010008792A1 (fr) * 2008-06-24 2010-01-21 Yale University Nanoparticules servant de plaquettes synthétiques et véhicules d'administration d'agent thérapeutique

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ATE179074T1 (de) 1999-05-15
ZA928607B (en) 1993-06-07
EP0667783A1 (fr) 1995-08-23
US5629294A (en) 1997-05-13
DE69229004D1 (de) 1999-05-27
TW269634B (fr) 1996-02-01
EP0667783A4 (fr) 1995-04-25
EP0667783B1 (fr) 1999-04-21
AU3064892A (en) 1993-06-07

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